Ophthalmic compositions for soft contact lens, method of enhancing wettability of soft contact lens, and method of inhibiting terpenoid adsorption

ABSTRACT

The present invention provides an ophthalmic composition for soft contact lenses (SCL), which contains a terpenoid as an active ingredient, an ophthalmic composition for SCL, which contains polyoxyethylene sorbitan ester, a method of enhancing the wettability of soft contact lenses, which comprises bringing terpenoid into contact with SCL and a method of inhibiting adsorption of terpenoid onto SCL, which comprises adding polyoxyethylene sorbitan ester to an ophthalmic composition containing a terpenoid. The ophthalmic composition containing a terpenoid improves, for example, the wettability of SCL, thereby to inhibit decrease in the water content of SCL. As a result, it can inhibit a dry feeling and an uncomfortable feeling during wearing SCL and is useful for enhancing the wettability of SCL. Further, addition of polyoxyethylene sorbitan ester leads to the inhibition of adsorption of terpenoid onto SCL.

This application is a 371 of PCT/JP98/03776 filed Aug. 24, 1998.

TECHNICAL FIELD

The present invention relates to an ophthalmic composition for softcontact lenses (hereinafter to be abbreviated as SCL). Moreparticularly, the present invention relates to a composition forenhancing the wettability of SCL, a method of enhancing the wettabilityof SCL and a method of inhibiting adsorption of terpenoid onto SCL.

BACKGROUND ART

SCL usually contains water and causes less uncomfortable feeling.However, a long-term use of the lens often causes a dry feeling. This isbecause when the water contained in the lens evaporates, precorneal tearfilm under SCL is affected and corneal stain occurs, and further, whenthe water content decreases, the curve of SCL and the like changes tohave a different lens standard. As a result, an uncomfortable feeling isenhanced.

A dry feeling and an uncomfortable feeling due to lower water contentare peculiar to SCL, and there is a demand for the solution to thisproblem of SCL.

It is therefore an object of the present invention to provide anophthalmic composition for SCL, such as a composition capable ofinhibiting a dry feeling, and an uncomfortable feeling caused by adecreased water content of SCL.

Another object of the present invention is to provide a method ofenhancing the wettability of SCL.

DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies in an attempt toachieve the above-mentioned objects and found that terpenoid can improvethe wettability of SCL, thus inhibiting a decrease in the water contentof SCL to eventually inhibit a dry feeling and an uncomfortable feeling,which resulted in the completion of the present invention.

Accordingly, the present invention provides the following.

(1) An ophthalmic composition for SCL, which contains a terpenoid as anactive ingredient.

(2) The ophthalmic composition of (1) above, which is for enhancing thewettability of SCL.

(3) The ophthalmic composition of (1) or (2) above, wherein theterpenoid is at least one member selected from the group consisting ofmenthol, borneol and camphor.

(4) The ophthalmic composition of any of (1) to (3) above, which is inthe form of an eye drop.

(5) The ophthalmic composition of any of (1) to (4) above, whichcontains polyoxyethylene sorbitan ester and which is in the form of aliquid when in use.

(6) The ophthalmic composition of any of (1) to (5) above, which is inthe form of a liquid having a pH of not less than 5.5 when in use.

(7) A method of enhancing the wettability of SCL, which comprisesbringing a terpenoid into contact with the SCL.

(8) The method of (7) above, wherein the terpenoid is at least onemember selected from the group consisting of menthol, borneol andcamphor.

(9) A method of inhibiting adsorption of terpenoid onto SCL, whichcomprises adding polyoxyethylene sorbitan ester to an ophthalmiccomposition which contains a terpenoid and which is in the form of aliquid when in use.

(10) A method of inhibiting adsorption of terpenoid onto SCL, whichcomprises adjusting a pH of an ophthalmic composition which contains aterpenoid and which is in the form of a liquid when in use, to not lessthan 5.5.

(11) The method of inhibiting adsorption of terpenoid onto SCL of (9) or(10) above, wherein the terpenoid is at least one member selected fromthe group consisting of menthol, borneol and camphor.

The terpenoid to be contained in the ophthalmic composition for SCL ofthe present invention may be a monoterepene such as menthol, borneol,camphor, geraniol, cineole, anethol, limonene, eugenol and the like, asesquiterpene such as farnesol, nerolidol and the like, a diterpene suchas phytol, cembrene and the like, or other terpenoid. Particularlypreferred are menthol, borneol, camphor and the like.

The content of the terpenoid to be contained in the ophthalmiccomposition for SCL of the present invention is 0.0001-0.2 (W/V) %,preferably 0.001-0.05 (W/V) %, when in use.

The ophthalmic composition for SCL of the present invention, whichcontains a terpenoid, can be used as a composition for any ophthalmicuse for SCL. To be specific, it can be used as a composition forenhancing the wettability of SCL, and the like.

The ophthalmic composition for SCL of the present invention can be usedin any form of a preparation generally used for topical application tothe eye. For example, it may be prepared into an eye drop, eye ointment,gel, solid preparation that becomes a liquid upon dissolution when inuse (e.g., tablet, powder, granule, freeze-dry preparation and thelike), and the like, with preference given to use in the form of an eyedrop. The eye drop may be aqueous or non-aqueous, and may be a solutionor suspension.

The SCL worn on an eye is washed with a tear fluid. Even if aningredient of the ophthalmic composition is adsorbed onto SCL, it isnormally washed away and rarely causes irritation to the eye, and thelike. However, the adsorption of each ingredient is desirably as smallas possible.

From this viewpoint, the present inventors have conducted variousstudies and found that (1) addition of polyoxyethylene sorbitan ester toan ophthalmic composition for SCL, which contains a terpenoid as anactive ingredient, and which becomes a liquid upon dissolution when inuse, and/or (2) adjustment of pH to not less than 5.5 when in useresult(s) in the inhibition of adsorption of terpenoid onto SCL.

Accordingly, the present invention relates to an ophthalmic compositionfor SCL, which contains a terpenoid as an active ingredient and whichbecomes a liquid upon dissolution when in use, and provides

(1) a composition containing polyoxyethylene sorbitan ester and/or

(2) a composition having a pH of not less than 5.5 when in use.

From a different aspect, the present invention provides the following.

(1) A method of inhibiting adsorption of terpenoid onto SCL, whichcomprises adding polyoxyethylene sorbitan ester to an ophthalmiccomposition which contains a terpenoid and which becomes a liquid upondissolution when in use.

(2) A method of inhibiting adsorption of terpenoid onto SCL, whichcomprises adjusting a pH when in use of an ophthalmic composition, whichcontains a terpenoid and which becomes a liquid upon dissolution when inuse, to not less than 5.5.

The ophthalmic composition for SCL of the present invention improves,for example, the wettability of SCL, thereby to inhibit a decrease inthe water content of SCL. As a result, it can inhibit a dry feeling andan uncomfortable feeling during wearing SCL and is useful for enhancingthe wettability of SCL.

In addition, (1) an ophthalmic composition which containspolyoxyethylene sorbitan ester and which becomes a liquid upondissolution when in use and (2) an ophthalmic composition which has anadjusted pH of not less than 5.5 and which becomes a liquid upondissolution when in use, are associated with less concern of irritationto the eye or an adverse influence such as cloudiness of SCL and thelike, since adsorption of terpenoid onto SCL is inhibited.

It is preferable that polyoxyethylene sorbitan ester be added to theconcentration when in use of 0.01-0.5 (W/v) %, preferably 0.05-0.2 (W/V)%.

Examples of preferable polyoxyethylene sorbitan ester includepolysorbate 80, polysorbates 20, 40, 60, 65, 85 and the like.

The inventive composition is adjusted to have a pH when in use of notless than 5.5, preferably not less than 5.5 and not more than 8. In thisway, the adsorption of terpenoid onto SCL can be inhibited. When the pHis not less than 5.5, terpenoid is hardly adsorbed onto SCL. When the pHis not less than 8, the composition becomes strongly alkaline and is notpreferable as an ophthalmic composition.

The pH is adjusted using a pH adjusting agent. Examples of the pHadjusting agent include hydrochloric acid, citric acid and a saltthereof (sodium citrate, sodium dihydrogencitrate and the like),phosphoric acid and a salt thereof (disodium hydrogenphosphate,potassium dihydrogenphosphate and the like), acetic acid and a saltthereof (sodium acetate, ammonium acetate and the like), tartaric acidand a salt thereof (sodium tartrate and the like), sodium hydroxide,potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, boricacid and a salt thereof (sodium borate) and the like.

The ophthalmic composition for SCL of the present invention can beprepared by adding a terpenoid and a base (e.g., solvent, ointment baseand the like), and further adding, according to the dosage form, variousadditives such as a solubilizer, buffer, isotonicity agent,preservative, stabilizer, thickener, adsorption inhibitor, chelatingagent, pH adjusting agent, suspending agent and the like, asappropriate, and following a known method.

Examples of solvent as a base include water (e.g., distilled water,sterile purified water, physiological saline and the like), alcohols(e.g., ethanol, propylene glycol, macrogol, glycerol and the like) andthe like.

Examples of solubilizer include polyvinylpyrrolidone, polyethyleneglycol, propylene glycol, polyoxyethylene hydrogenated castor oil 60,polyoxyl 40 stearate and the like.

A buffer is used to make the pH of the inventive ophthalmic compositionfor SCL approximately 5-9, preferably 6-8. For example, used are boricacid or a salt thereof (sodium borate and the like), citric acid or asalt thereof (sodium citrate and the like), tartaric acid or a saltthereof (sodium tartrate and the like), gluconic acid or a salt thereof(sodium gluconate and the like), acetic acid or a salt thereof (sodiumacetate and the like), phosphoric acid or a salt thereof (sodiumhydrogenphosphate, sodium dihydrogenphosphate and the like), variousamino acids and the like or a combination thereof.

The isotonicity agent may be, for example, sorbitol, glucose, mannitol,glycerol, propylene glycol, sodium chloride, potassium chloride and thelike.

Examples of preservative include p-hydroxybenzoates, benzalkoniumchloride, benzetonium chloride, chlorobutanol, benzyl alcohol, sorbicacid or a salt thereof, chlorhexidine gluconate, sodium dehydroacetate,cethylpyridinium chloride, alkyldiaminoethylglycine hydrochloride andthe like.

Examples of stabilizer include ascorbic acid, sodium edetate,cyclodextrin, condensed phosphoric acid or a salt thereof, sulfite,citric acid or a salt thereof and the like.

Examples of thickener include methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium chondroitinsulfate, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol and the like.

Examples of chelating agent include sodium edetate, sodium citrate,condensed phosphoric acid or a salt thereof (condensed sodium phosphateand the like) and the like.

Examples of suspending agent include methylcellulose,hydroxypropylcellulose, polyvinylpyrrolidone, polyoxyethylenehydrogenated castor oil 60, polyoxyl 40 stearate, polyethylene glycol,sodium carboxymethylcellulose, polyvinyl alcohol and the like.

As long as the object of the present invention is not impaired, theinventive ophthalmic composition for SCL may further contain anefficacious ingredient such as vitamins (e.g., retinol palmitate,pyridoxine hydrochloride, tocopherol acetate and the like), angiotonic(e.g., naphazoline hydrochloride, tetrahydrozoline hydrochloride and thelike), antiinflammatory agent (e.g., dipotassium glycyrrhizinate, sodiumazulenesulfonate and the like), and the like as appropriate.

The dose of the ophthalmic composition for SCL of the present inventionwhen used as an eye drop to an adult, which contains a terpenoid as anactive ingredient in 0.0001-0.2 (W/V) %, preferably 0.001-0.05 (W/v) %,is preferably 2 or 3 drops per administration which is given 5 or 6times a day.

EXAMPLES

The present invention is explained in more detail in the following byway of Examples and Experimental Examples to demonstrate the effect ofthe present invention, which Examples are for the purpose ofexemplification only, and do not limit the present invention in any way.

Example 1

An eye drop of the following recipe was prepared according to aconventional method.

potassium chloride 0.15 g sodium chloride 0.55 g boric acid 0.5 g sodiumborate 0.55 g sorbic acid 0.1 g sodium edetate 0.01 g 1-menthol 0.002 ghydroxyethylcellulose 0.1 g polysorbate 80 0.15 g sterile purified waterappropriate amount total amount 100 ml (pH 7.3)

Example 2

An eye drop of the following recipe was prepared according to aconventional method.

potassium chloride 0.15 g sodium chloride 0.55 g boric acid 0.5 gchlorhexidine gluconate solution (20 W/V%) 0.025 ml (0.005 g aschlorhexidine gluconate) sodium edetate 0.01 g 1-menthol 0.002 ghydroxyethylcellulose 0.1 g polysorbate 80 0.15 g sterile purified waterappropriate amount sodium hydroxide appropriate amount total amount 100ml (pH 7.3)

Example 3

An eye drop of the following recipe was prepared according to aconventional method.

potassium chloride 0.15 g sodium chloride 0.55 g boric acid 0.5 gchlorhexidine gluconate solution (20 W/V%) 0.025 ml (0.005 g aschlorhexidine gluconate) sodium edetate 0.01 g 1-menthol 0.002 ghydroxyethylcellulose 0.1 g polysorbate 80 0.15 g boric acid 0.05 gsterile purified water appropriate amount total amount 100 ml (pH 7.3)

Experimental Example 1

Wettability Test

Test solutions of the following recipes were prepared.

Test Solution A:

Test solution A: polysorbate 80 1 g 1-menthol 0.2 g sterile purifiedwater appropriate amount total amount 100 ml Test solution B:polysorbate 80 1 g sterile purified water appropriate amount totalamount 100 ml

The above-mentioned Test solution A and Test solution B wererespectively dropped onto the following SCL (one lens) previously dried,and an angle formed by the droplet with the surface of the SCL at thepart in contact with the surface was measured at the beam using acontact angle measuring device [ERMA Goniometer type Contact Anglemeter,M-2010A-A (manufactured by ERMA)] to give a contact angle. (SCL used)

SCL (No. 1)

Main material: methyl methacrylate+N-vinylpyrrolidone

SCL (No. 2)

Main material: methyl methacrylate+glyceryl methacrylate

The obtained angles of contact are shown in Table 1.

TABLE 1 angle of contact SCL (No. 1) SCL (No. 2) Test solution A 17° 31°Test solution B 23° 44°

The angles of contact were smaller when the test solutions containing1-menthol were dropped onto SCLs No. 1 and No. 2. The results revealthat the addition of a terpenoid could improve the wettability of SCL.

Experimental Example 2

Inhibition of Dry Feeling and Uncomfortable Feeling

Two or three drops of the eye drop obtained in Example 1 were instilledinto either eye of the test subjects (8 persons) wearing SCL, and 2 or 3drops of the Test solution C of the following formula were instilledinto the other eye. The respective eyes were examined for changes in adry feeling and an uncomfortable feeling due to SCL.

A test solution of the following recipe was prepared according to aconventional method and used as Test solution C.

potassium chloride 0.15 g sodium chloride 0.55 g boric acid 0.5 g sodiumborate 0.55 g sorbic acid 0.1 g sodium edetate 0.01 ghydroxyethylcellulose 0.1 g polysorbate 80 0.15 g sterile purified waterappropriate amount total amount 100 ml (pH 7.3)

The obtained results were evaluated by giving points as mentioned below.The results with regard to dry feeling are shown in Table 2, and theresults with regard to uncomfortable feeling are shown in Table 3.

Evaluation Method:

5 points: The dry feeling or uncomfortable feeling vanished.

4 points: The dry feeling or uncomfortable feeling almost vanished.

3 points: The dry feeling and uncomfortable feeling did not change.

2 points: The dry feeling or uncomfortable feeling became rather severe.

1 point: The dry feeling or uncomfortable feeling became severe.

TABLE 2 dry feeling Administration of eye drop of Administration of TestTest subject Example 1 solution C No. 1 4 2 No. 2 5 3 No. 3 4 3 No. 4 53 No. 5 5 3 No. 6 4 4 No. 7 4 3 No. 8 5 3

TABLE 3 uncomfortable feeling Administration of eye drop ofAdministration of Test Test subject Example 1 solution C No. 1 4 3 No. 25 3 No. 3 4 3 No. 4 4 4 No. 5 4 3 No. 6 5 3 No. 7 5 3 No. 8 4 3

Experimental Example 3

Inhibition of Adsorption of Terpenoid onto SCL

Test solutions of the following recipes were prepared.

Test solution A: 1-menthol 0.002 g polysorbate 80 0.15 ml sterilepurified water appropriate amount total amount 100 ml Test solution B:1-menthol 0.002 g sterile purified water appropriate amount total amount100 ml

The above-mentioned Test solution A and Test solution B wererespectively measured by precisely 4 ml in vials and SCL (two SCLs) wereimmersed therein. A solution into which SCL was not immersed was used asa control test solution. The solutions were shaken at room temperaturefor 14 hours and the content of 1-menthol was measured. The differencefrom the control test solution was taken as the amount of adsorptiononto SCL. 1-Menthol was extracted with chloroform and quantitativelyassayed by gas chromatography.

(SCL Used)

Main material: hydroxyethyl methacrylate+methacrylic acid

The obtained results are as shown in Table 4.

The values in the Table are the total of the two SCLs.

TABLE 4 Test solution A 3.9 μg/lens Test solution B 5.9 μg/lens

The eye instilled with the eye drop of Example 1 was free of the dryfeeling and uncomfortable feeling due to SCL, but the eye instilled withTest solution C without terpenoid showed almost no changes.

The results reveal that the use of the ophthalmic composition containinga terpenoid of the present invention could suppress the dry feeling anduncomfortable feeling due to SCL.

The composition containing polyoxyethylene sorbitan ester showedsuppressed adsorption of terpenoid onto SCL.

Experimental Example 4

Test of Influence of Osmotic Pressure and pH

Test solutions of the following recipes were prepared.

Test solution A: 1-menthol 0.002 g sodium phosphate 2H₂O  0.5 g sodiumhydroxide or hydrochloric acid appropriate amount sterile purified waterappropriate amount total amount   100 ml (pH 4.5) Test solution B:1-menthol 0.002 g sodium phosphate 2H₂O  0.5 g sodium hydroxide orhydrochloric acid appropriate amount sterile purified water appropriateamount total amount   100 ml (pH 5.5) Test solution C: 1-menthol 0.002 gsodium phosphate 2H₂O  0.5 g sodium hydroxide or hydrochloric acidappropriate amount sterile purified water appropriate amount totalamount   100 ml (pH 6) Test solution D: 1-menthol 0.002 g sodiumphosphate 2H₂O  0.5 g sodium hydroxide or hydrochloric acid appropriateamount sterile purified water appropriate amount total amount   100 ml(pH 7) Test solution E: 1-menthol 0.002 g disodium phosphate 12H₂O  0.5g sodium hydroxide or hydrochloric acid appropriate amount sterilepurified water appropriate amount total amount   100 ml (pH 8)

The above recipes were respectively measured by precisely 2.5 ml invials and two SCLs were immersed therein. A solution, into which SCL wasnot immersed, was used as a control test solution. The solutions wereshaken at room temperature for 38 hours and 1-menthol was extracted withchloroform and quantitatively assayed by gas chromatography.

(SCL Used)

Main material: hydroxyethyl methacrylate+methacrylic acid

Water content: 58.0%

The obtained results are as shown in Table 5.

The values in the Table are the total of the two SCLs.

TABLE 5 Test solution A (pH 4.5) 9.5 μg/lens Test solution B (pH 5.5)7.3 μg/lens Test solution C (pH 6) 7.1 μg/lens Test solution D (pH 7)7.3 μg/lens Test solution E (pH 8) 6.3 μg/lens

INDUSTRIAL APPLICABILITY

The ophthalmic composition for SCL of the present invention improves,for example, the wettability of SCL, thereby to inhibit decrease in thewater content of SCL. As a result, it can inhibit a dry feeling and anuncomfortable feeling during wearing SCL and is useful for enhancing thewettability of SCL.

In addition, (1) an ophthalmic composition which containspolyoxyethylene sorbitan ester and which becomes a liquid when in useand (2) an ophthalmic composition which has an adjusted pH of not lessthan 5.5 and which becomes a liquid when in use, are associated withless concern of irritation to the eye and an adverse influence such ascloudiness of SCL and the like, since adsorption of terpenoid onto SCLis inhibited

This application is based on application Nos. 229775/1997 and195800/1998 filed in Japan, the contents of which are incorporatedhereinto by reference.

What is claimed is:
 1. A method of inhibiting adsorption of a terpenoidonto a soft contact lens, which comprises contacting a soft contact lenswith an eye drop comprising a terpenoid and a polyoxyethylene sorbitanester.
 2. A method of inhibiting adsorption of a terpenoid onto a softcontact lens, which comprises contacting a soft contact lens with an eyedrop comprising a terpenoid and having a pH of not less than 5.5.
 3. Themethod of inhibiting adsorption of terpenoid onto soft contact lens ofclaim 1, wherein the terpenoid is at least one member selected from thegroup consisting of menthol, borneol and camphor.
 4. The method ofinhibiting adsorption of terpenoid onto soft contact lens of claim 2,wherein the terpenoid is at least one member selected from the groupconsisting of menthol, borneol and camphor.
 5. The method of claim 1,wherein said terpenoid is a monoterpene.
 6. The method of claim 2,wherein said terpenoid is a monoterpene.
 7. The method of claim 1,wherein said terpenoid has a concentration of 0.0001 to 0.2 (w/v)%. 8.The method of claim 2, wherein said terpenoid has a concentration of0.0001 to 0.2 (w/v)%.
 9. The method of claim 1, wherein saidpolyoxyethylene sorbitan ester has a concentration of 0.01 to 0.5(w/v)%.
 10. The method of claim 2, wherein the soft contact lens furthercontacting with polyoxyethylene sorbitan ester having a concentration of0.01 to 0.5 (w/v)%.